The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophene with diethyl malonate: Synthesis of coumarin, pyridine, and thiazole derivatives

Article abstract of DOI:10.1002/hc.1027

The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (1) with diethyl malonate (2) gave two products: 3 and 4. The reactivity of 3 toward a variety of chemical reagents was studied to give azoles, azines, and their fused derivatives.

Full text of DOI:10.1002/hc.1027

Heteroatom Chemistry
Volume 12, Number 3, 2001
The Reaction of 2-Amino-3-cyano-4,5,6,7-
Tetrahydrobenzo[b]-thiophene with Diethyl
Malonate: Synthesis of Coumarin, Pyridine,
and Thiazole Derivatives
Rafat M. Mohareb,1 Fatma A. El-Omran,2 and Jonathan Z. Ho1
1Department of Chemistry, University of California, Berkeley, CA 94720
2Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969 Safat, 13060 Kuwait
Received 22 November 2000; revised 29 December 2000
diethyl malonate 2 to form 2-amidothiophene deriv-
ABSTRACT: The reaction of 2-amino-3-cyano-
atives capable of heterocyclization when reacted
with a variety of chemical reagents. Thus, the reac-
4,5,6,7-tetrahydrobenzo[b]thiophene (1) with diethyl
malonate (2) gave two products: 3 and 4. The reactiv-
tion of 1 with 2 in an oil bath at 140ЊC gave two
ity of 3 toward a variety of chemical reagents was stud-
products, each with the molecular formula
ied to give azoles, azines, and their fused derivatives.
C14H16N2SO3. Their separation was based on the
᭧ 2001 John Wiley & Sons, Inc. Heteroatom Chem
greater solubility of one of the products over the
12:168–175, 2001
other in ethanol. The ethanol soluble product was
identified to be compound 3, based on analytical and
spectral data. Thus, the IR spectrum showed the CN
INTRODUCTION
group stretching at 2225 cmמ1, together with two
very strong CסO stretching signals at 1745 and 1695
cmמ1. Moreover, the 13C NMR data showed the pres-
ence of d 28.4 (ester CH3), 29.7, 30.6 (cyclohexene C-
1, C-4), 24.1, 24.7 (cyclohexene C-2, C-3), 52.9 (ester
CH2), 58.6 (CH2), 119.9 (CN), 126.6, 132.1, 132.7,
138.0 (thiophene-C), 178.9 and 181.0 (2 CסO). The
ethanol insoluble product (low yield) was identified
to be the tetrahydrobenzo[b]thieno[5,4:2,3]pyridine
derivative 4. The IR spectrum of the latter compound
Over recent years we have been involved in a com-
prehensive program aimed at investigating the re-
actions of 4,5,6,7-tetrahydrobenzo[b]thiophene de-
rivatives with a variety of chemical reagents with
subsequent heterocyclization of the products to
form pyridines, pyrimidines, and pyridazines [1–3].
The importance of such compounds is due to their
diverse pharmaceutical activities including antibac-
terial [4], antidiabetic [5], anti-inflammatory [6],
and antiviral [7,8], and as antiplatelet activating fac-
tors [9].
1
showed no CN stretching. Moreover, the H NMR
spectrum showed, in addition to the characteristic
signals of the tetrahydrobenzene ring, a triplet at d
1.33 for the CH3 group, a quartet at d 4.28 for the
ester CH2 group, and a singlet (D2O exchangeable) at
d 5.23 corresponding to the NH2 group. Moreover,
the 13C NMR data showed d 27.8 (ester CH3), 29.5,
30.2 (cyclohexene C-1, C-4), 23.8, 24.9 (cyclohexene
C-2, C-3), 53.2 (ester CH2), 120.7 (CN), 126.4, 132.0,
132.2, 134.2, 134.9, 138.7, 138.9, 140.2 (thiophene-
RESULTS AND DISCUSSION
In this article, we report the reaction of 2-amino-3-
cyano-4,5,6,7-tetrahydrobenzo[b]thiophene 1 with
Correspondence to: Rafat M. Mohareb.
᭧ 2001 John Wiley & Sons, Inc.
168

The Reaction of 2-Amino-3-cyano-4,5,6,7-Tetrahydrobenzo[b]-thiophene with Diethyl Malonate 169
C, pyridine-C), and 181.7 (CסO). Compound 3
NMR data showed d 26.3 (ester CH3), 29.3, 30.7 (cy-
clohexane C-1, C-4), 22.7, 25.4 (cyclohexane C-2, C-
3), 55.2 (ester CH2), 125.2, 131.5, 132.8, 133.1, 133.6,
136.2, 138.9, 140.5, 143.2, 143.7 (thiophene-C, py-
rimidine-C, pyridine-C), 179.6, and 180.4 (2 CסO)
(Scheme 2).
showed interesting reactivity toward a variety of
chemical reagents. Thus, it reacted with benzenedi-
azonium chloride at 0ЊC to give the corresponding
hydrazone derivative 5. The latter reacted with hy-
drazine hydrate to give the 5-hydroxy-1,2,3-triazole
derivative 6. The structure of compound 6 was based
on analytical and spectral data (see Experimental
section). The reaction of compound 3 with benzal-
dehyde gave the benzal derivative 7. The latter re-
acted with hydrazine hydrate and phenylhydrazine
to give the 3-hydroxypyrazole derivatives 8a and 8b,
respectively, (Scheme 1). The reaction of 3 with sal-
icylaldehyde gave the coumarin derivative 9, the for-
mation of which took place through first a conden-
sation followed by ethanol elimination (Scheme 2).
The reactivity of compound 3 toward cyanome-
thylene reagents was studied. Thus, with either ma-
lononitrile (10a) or ethyl cyanoacetate (10b), the
corresponding 2-pyridinyl-4,5,6,7-tetrahydrobenzo
[b]thiophene derivatives 11a and 11b, respectively,
were formed. Compound 11a underwent ready cy-
clization when heated in a boiling water bath with
sodium ethoxide solution to give the annulated com-
pound, which was identified as the tetrahydroben-
zo[b]thieno[2,3:4,5]pyrimidino[3,2:1,2]pyridine de-
rivative 12. The structure of compound 12 was
identified on the basis of the disappearance of CN
group stretching in the IR spectrum, and the 13C
Compound 3 reacted with bromine in hot acetic
acid solution to give the monobromo derivative 13
(Scheme 2). The latter reacted with potassium cya-
nide in ethanol solution to give the tetrahydro-
benzo[b]thieno[2,3-b]pyridine derivative 15. Com-
pound 15 was formed through the intermediate
formation of 14 followed by cyclization. The IR spec-
trum of 15 showed only one CN group stretching at
מ1
tמ 2225 cm and two CסO group stretchings at tמ
1715 and tמ 1683 cmמ1. The reaction of compound
13 with thiourea gave the 2-aminothiazole derivative
16, the structure of which was established on the
basis of analytical and physical data (see Experi-
mental section. Compound 16 underwent ready
cyclization when heated in ethanolic sodium hy-
droxide solution to give the tetrahydrobezo[b]
thieno[5,4:2,3]pyridino[6,5;4,5]-thiazolidene deriva-
tive 18. Formation of the latter product took place
through the intermediate formation of 17 followed
by ester hydrolysis and decarboxylation. 13C NMR
data confirm its structure; thus, d 26.9 (ester CH3),
29.2, 30.9 (cyclohexene C-1, C-4), 24.2, 24.5 (cyclo-
hexene C-2, C-3), 52.9 (ester CH2), 119.2 (CN), 124.5,
130.7, 131.9, 134.9, 140.2, 142.8 (thiophene-C, pyri-
dine-C), 179.8, 180.7 (2 CסO) (Scheme 3).
SCHEME 1
SCHEME 2

170 Mohareb, El-Omran, and Ho
SCHEME 3
SCHEME 4
expected signal of the cyclohexene ring, a singlet at
d 2.20 for the CH3 group, a multiplet at d 7.29–7.34
attributable to the phenyl protons, two singlets (D2O
exchangeable) at d 8.45 and 8.59 for two NH groups,
and a singlet at d 10.62 for an OH group. Moreover,
the 13C NMR data showed d 29.2, 31.0 (cyclohexene
C-1, C-4), 24.3, 24.8 (cyclohexene C-2, C-3), 120.1
(CN), 122.0, 122.9, 124.4, 130.8, 131.6, 132.7, 134.9,
136.7, 136.9, 140.0 (two thiophene-C, benzene-C),
178.9, and 180.4 (CסO). However, the reaction of 24
with either phenacyl bromide 27a or ethyl bromo-
acetate 27b gave the thiazole derivatives 28a and
28b, respectively. The structures of the latter prod-
ucts were based on analytical and spectral data (see
Experimental section) (Scheme 5).
Compound 3 reacted with thioglycolic acid to
give the thiazole derivative 19. The latter product un-
derwent ready cyclization when heated in dimeth-
ylformamide solution containing a catalytic amount
of triethylamine to give the tetrahydrobenzo[b]
thieno[5,4:4,5]pyrimidino[6,1:2,3]thiazole deriva-
tive 20. Moreover, the reaction of compound 3 with
cinnamonitrile derivatives was studied. Thus, the re-
action of 3 with either ␣-cyanocinnamonitrile (21a)
or ␣-ethoxycarbonyl cinnamonitrile (21b) gave the
2-pyridino-4,5,6,7-tetrahydrobenzo[b]thiophene de-
rivatives 22a and 22b, respectively. The latter prod-
ucts underwent ready cyclization when heated in
sodium ethoxide solution to give the tetrahydroben-
zo[b]thieno[5,4:4,5]pyrimidino[3,2:1,2pyridine de-
rivatives 23a and 23b, respectively. The structures of
compounds 22a,b and 23a,b were based on analyti-
cal and spectral data (see Experimental section)
(Scheme 4).
EXPERIMENTAL
All melting points were uncorrected. IR spectra were
recorded (KBr) on a Pye Unicam Sp-1000 spectro-
1
photometer. H NMR and 13C NMR spectra were
Our research group has studied the reaction of
active methylene reagents with phenyl isothiocya-
nate in basic dimethylformamide/KOH solution, fol-
lowed by heterocyclization with ␣-halocarbonyl
compounds to give either thiophene or thiazole de-
rivatives [10–13]. The nature of the products de-
pends on the ␣-halocarbonyl compound used. In a
similar way, the reaction of compound 3 with phenyl
isothiocyanate in basic dimethylformamide solution
gave the intermediate potassium sulfide salt 24. The
reaction of 24 with chloroacetone 25 gave the thio-
measured on a Varian EM-390 90 Mhz spectrometer
in DMSO-d6 as solvent and TMS as an internal ref-
erence. Chemical shifts were expressed as d. Analyt-
ical data were carried out at the Microanalytical
Data Unit at Cairo University.
3-Cyano-2-(ethoxycarbonylacetamido-N-yl)-
4,5,6,7-tetrahydrobenzo[b]thiophene 3 and 4-
Amino-3-ethoxycabonyl-2-hydroxy-4,5,6,7-
tetrahydro[b]thieno[5,4:2,3]pyridine 4
1
phene derivative 26. Its structure was based on H
General Procedure. To the dry solid 1 (1.78 g,
NMR spectral data that showed, in addition to the
0.01 mol), diethyl malonate (1.52 g, 0.01 mol) was

The Reaction of 2-Amino-3-cyano-4,5,6,7-Tetrahydrobenzo[b]-thiophene with Diethyl Malonate 171
3-Cyano-2-[␣-ethoxycarbonyl-␣-
phenylhydrazoactamido-N-yl]-4,5,6,7-
tetrahydrobenzo[b]thiophene 5
To a cold solution (0–5ЊC) of 3 (2.92 g, 0.01 mol) in
ethanol (40 mL), a cold solution of benzenediazon-
ium chloride (0.01 mol) (prepared by adding cold
sodium nitrilte solution [0.7 g, 0.01 mol] to a cold
suspension [0–5ЊC] of aniline [0.92 g, 0.01 mol] in
concentrated hydrochloric acid [8 ml] with stirring)
was added with continuous stirring. The whole re-
action mixture was left at room temperature for 4
hours, and the formed solid product was collected
by filtration.
5: Red crystals (from ethanol), yield 80% (3.16
g), m.p. 165ЊC. IR (tמ/cmמ1) ס 3460–3310 (NH),
2980, 2970 (CH3, CH2), 2220 (CN), 1705, 1685 (2
SCHEME 5
1
CסO), 1640 (CסC). H NMR d ס 1.36 (t, 3H, CH3),
2.26, 2.79 (2m, 8H, 4CH2), 4.23 (q, 2H, CH2), 8.99,
9.67 (2s, 2H, 2NH). C20H20N4O3S (396.44); Calcd: C,
60.59; H, 5.08; N, 14.13; S, 8.09; found: C, 60.46; H,
4.87, N, 14.45; S, 7.77.
added. The reaction mixture was heated in an oil
bath at 140ЊC for 2 hours and then left to cool. Eth-
anol (50 mL, 95%) was added to the reaction mix-
ture, and the whole mixture was heated and filtered.
The ethanol-soluble product was collected from the
filtrate, precipitated upon addition of ice containing
a few drops of hydrochloric acid, and identified. This
solid product was identified as compound 1. The
ethanol insoluble product was identified as com-
pound 4.
3: Yellowish white crystals (from ethanol), yield
76% (2.21 g), m.p. 220–222ЊC. IR (tמ/cmמ1) ס 3450–
3230 (NH), 2986, 2960 (CH3, CH2), 2225 (CN), 1745,
1695 (2 CסO), 1645 (CסC). 1H NMR d ס 1.31 (t, 3H,
CH3), 2.24, 2.78 (2m, 8H, 4CH2), 4.25 (q, 2H, CH2),
5.67 (s, 2H, CH2), 8.89 (s, 1H, NH). 13C NMR d ס 28.4
(ester CH3), 29.7, 30.6 (cyclohexene C-1, C-4), 24.1,
24.7 (cyclohexene C-2, C-3), 52.9 (ester CH2), 58.6
(CH2) 119.9 (CN), 126.6, 132.1, 132.7, 138.0 (thio-
phene-C), 178.9, 181.0 (2 CסO). C14H16N2O3S
(292.34): Calcd: C, 57.52; H, 5.51; N, 9.59; S, 10.97;
found: C, 57.31; H, 5.59, N, 9.23; S, 11.21.
3-Cyano-2-aminocarbonyl[4-hydroxy-2-phenyl-
1,2,3-triazol-5-yl]-4,5,6,7-
tetrahydrobenzo[b]thiophene 6
To a solution of 5 (3.96 g, 0.01 mol) in 1,4-dioxane
(50 mL), hydrazine hydrate (0.5 ml, 0.01 mol) is
added. The reaction mixture was heated under reflux
for 5 hours and evaporated in a vacuum, and the
remaining product was triturated with ethanol. The
formed solid product was collected by filtration.
6: Yellow crystals (from acetic acid), yield 66%
(2.40 g), m.p. 185ЊC. IR (tמ/cmמ1) ס 3530–3300 (OH,
NH), 3060 (CH aromatic), 2976 (CH2), 2220 (CN),
1
1690 (CסO), 1655, 1635 (CסC). H NMR d ס 2.25,
2.69 (2m, 8H, 4CH2), 7.32–7.39 (m, 5H, C6H5), 8.53
(1s, 1H, NH). C18H15N5O2S (365.39): Calcd: C, 59.17;
H, 4.14; N, 19.16; S, 8.78; found: C, 59.46; H, 4.86,
N, 19.45; S, 9.01.
4: Yellow crystals (from 1,4-dioxane), yield 15%
(0.43 g), m.p. Ͼ 300ЊC. IR (tמ/cmמ1) ס 3570–3330
(OH, NH2), 2980, 2973 (CH3, CH2), 1680 (CסO),
3-Cyano-2-[␣-ethoxycarbonyl-␣-benzalactamido-
N-yl]-4,5,6,7-tetrahydrobenzo[b]thiophene 7 and
3-Cyano-2-aminocarbonyl[coumarin-3-yl]-
4,5,6,7-tetrahydrobenzo[b]thiophene 9
1
1640 (CסC). H NMR d ס 1.33 (t, 3H, CH3), 2.23,
2.74 (2m, 8H, 4CH2), 4.28 (q, 2H, CH2), 5.32 (s, 2H,
NH2), 10.21 (s, 1H, OH). 13C NMR d ס 27.8 (ester
CH3), 29.5, 30.2 (cyclohexene C-1, C-4), 23.8, 24.9
(cyclohexene C-2, C-3), 53.2 (ester CH2), 120.7
(CN), 126.4, 132.0, 132.2, 134.2, 134.9, 138.7, 138.9,
140.2 (thiophene-C, pyridine-C), 181.7 (CסO).
C14H16N2O3S (292.34): Calcd: C, 57.52; H, 5.51; N,
9.59; S, 10.97; found: C, 57.20; H, 5.42, N, 9.69; S,
10.77.
General Procedure. To a solution of 3 (2.92 g,
0.01 mol) in 1,4-dioxane (50 mL) containing piperi-
dine (0.5 mL), either benzaldehyde (1.02 g, 0.01 mol)
or salicylaldehyde (1.18 g, 0.01 mol) was added. The
reaction mixture, in each case, was heated under re-
flux for 4 hours and then evaporated in a vacuum.

172 Mohareb, El-Omran, and Ho
The remaining product was triturated with diethyl
ether, and the formed solid product was collected by
filtration.
3-Cyano-2-(2,4-diamino-5-ethoxycarbonyl-6-
oxopyridine-1-yl)-4,5,6,7-tetrahydrobenzo
[b]thiophene 11a, 3-Cyano-2-(4-amino-5-
ethoxycarbonyl-2-hydroxy-6-oxopyridine-1-yl)-
4,5,6,7-tetrahydro-benzo[b]thiophene 11b, 3-
Cyano-2-(2-amino-3-cyano-5-ethoxycarbonyl-
4-phenyl-6-oxopyridine-1-yl)-4,5,6,7-tetrahydro-
benzo[b]thiophene 22a, and 3-Cyano-2-
(2-amino-3,5-diethoxycarbonyl-4-phenyl-6-oxo-
pyridine-1-yl)-4,5,6,7-tetrahydro-benzo[b]
thiophene 22b
7: White crystals (from ethanol), yield 71% (2.69
g), m.p. 265–267ЊC IR (tמ/cmמ1) ס 3500–3350 (NH),
3065 (CH aromatic), 2979, 2880 (CH3, CH2), 2222
1
(CN), 1705, 1685 (2 CסO), 1645 (CסC). H NMR d
ס 1.37 (t, 3H, CH3), 2.27, 2.70 (2m, 8H, 4CH2), 4.23
(q, 2H, CH2), 6.67 (s, 1H, CHסC), 7.30–7.37 (m, 5H,
C6H5), 8.75 (s, 1H, NH). C21H20N2O3S (380.44): Calcd:
C, 66.30; H, 5.30; N, 7.36; S, 8.43%, found: C, 66.01;
H, 4.96, N, 7.21; S, 9.30%.
General Procedure. A solution of 3 (2.92 g, 0.01
mol) in dimethylformamide (40 mL) containing tri-
ethylamine (0.5 mL) was treated with either malon-
onitrile (0.66 g, 0.01 mol), ethyl cyanoacetate (1.13
g, 0.01 mol), ␣-cyanocinnamonitrile (1.74 g, 0.01
mol), or ␣-ethoxycarbonyl cinnamonitrile (2.21 g,
0.01 mol). The reaction mixture, in each case, was
heated under reflux for 6 hours and then poured into
ice/water containing a few drops of hydrochloric
acid. The solid product, formed in each case, was
collected by filtration.
9: Yellow crystals (from 1,4-dioxane), yield 90%
(3.15 g), m.p. 230–234ЊC. IR (tמ/cmמ1) ס 3500–3310
(NH), 3066 (CH aromatic), 2976 (CH2), 2223 (CN),
1708, 1685 (2 CסO), 1648 (CסC). 1H NMR d ס 2.27,
2.73 (2m, 8H, 4CH2), 6.99 (s, 1H, coumarin H-9),
7.33–7.41 (m, 4H, C6H4), 8.83 (1s, 1H, NH).
C19H14N2O3S (350.37): Calcd: C, 65.13; H, 4.03; N,
7.99; S, 9.15; found: C, 65.09; H, 4.47, N, 8.51; S, 9.47.
11a: Orange crystals (from acetic acid), yield
86% (3.01 g), m.p. 240–243ЊC. IR (tמ/cmמ1) ס 3480–
3320 (2 NH2), 3030 (CH pyridine), 2980, 2880 (CH3,
CH2), 2225 (CN), 1690, 1680 (2 CסO), 1640 (CסC).
1H NMR d ס 1.31 (t, 3H, CH3), 2.21, 2.69 (2m, 8H,
4CH2), 4.21 (q, 2H, CH2), 4.68, 5.62 (2s, 4H, 2NH2),
6.99 (s, 1H, pyridine H-3), C17H18N4O3S (358.39):
Calcd: C, 56.97; H, 5.06; N, 15.63; S, 8.94; found: C,
56.75; H, 4.77, N, 15.61; S, 9.23.
11b: Orange crystals (from acetic acid), yield
60% (2.15 g), m.p. 155–157ЊC. IR (tמ/cmמ1) ס 3580–
3300 (OH, NH2), 3036 (CH pyridine), 2988, 2889
(CH3, CH2), 2222 (CN), 1694 (CסO), 1648 (CסC). 1H
NMR d ס 1.33 (t, 3H, CH3), 2.25, 2.65 (2m, 8H,
4CH2), 4.25 (q, 2H, CH2), 5.62 (s, 2H, NH2), 7.03 (s,
1H, pyridine H-5), C17H17N3O4S (359.38): Calcd: C,
56.81; H, 4.76; N, 11.69; S, 8.92; found: C, 56.77; H,
4.79, N, 11.68; S, 9.09.
3-Cyano-2-aminocarbonyl[3-hydroxy-5-
phenylpyrazol-4-yl]-4,5,6,7-tetrahydrobenzo[b]
thiophene 8a and 3-Cyano-2-aminocarbonyl[3-
hydroxy-1,5-diphenylpyrazol-4-yl]-4,5,6,7-
tetrahydrobenzo[b]thiophene 8b
General Procedure. To a solution of 7 (3.80 g,
0.01 mol) in dimethylformamide (30 mL), either hy-
drazine hydrate (0.5 mL, 0.01 mol) or phenylhydra-
zine (1.10 g, 0.01 mol) was added. The reaction mix-
ture was heated under reflux for 5 hours and then
poured into ice containing a few drops of hydrochlo-
ric acid. The solid product, formed in each case, was
collected by filtration,
8a: Orange crystals (from acetic acid), yield 78%
(3.03 g), m.p. 145ЊC. IR (tמ/cmמ1) ס 3560–3340 (OH,
NH), 3058 (CH aromatic), 2979 (CH2), 2220 (CN),
1
1693 (CסO), 1660 (CסN), 1646 (CסC), H NMR d
ס 2.25, 2.71 (2m, 8H, 4CH2), 7.29–7.35 (m, 5H,
C6H5), 8.79, 9.41 (2s, 2H, 2NH), 10.63 (s, 1H, OH).
C19H16N4O2S (364.41): Calcd: C, 62.62; H, 4.43; N,
15.37; S, 8.79; found: C, 62.39; H, 4.17, N, 15.61; S,
9.20.
22a: Yellow crystals (from 1,4-dioxane), yield
82% (3.64 g), m.p. 220–223ЊC. IR (tמ/cmמ1) ס 3420,
3380 (NH2), 3050 (CH aromatic), 2988, 2870 (CH3,
CH2), 2225, 2220 (2 CN), 1695, 1687 (2 CסO), 1644
1
(CסC). H NMR d ס 1.33 (t, 3H, CH3), 2.26, 2.71
8b: Orange crystals (from acetic acid), yield 63%
(2.78g), m.p. 188ЊC. IR (tמ/cmמ1) ס 3557–3321 (OH,
NH), 3060 (CH aromatic), 2982 (CH2), 2225 (CN),
(2m, 8H, 4CH2), 4.25 (q, 2H, CH2), 4.55 (s, 2H, NH2),
7.32–7.37 (m, 5H, C6H5), C24H20N4O3S (444.64):
Calcd: C, 64.86; H, 4.53; N, 12.60; S, 7.21; found: C,
64.77; H, 4.67, N, 12.67; S, 7.09.
1
1687 (CסO), 1666 (CסN), 1642 (CסC). H NMR d
ס 2.22, 2.76 (2m, 8H, 4CH2), 7.31–7.39 (m, 10H,
2C6H5), 9.21 (s, H, NH), 10.57 (s, 1H, OH).
C25H20N4O2S (440.51): Calcd: C, 68.16; H, 4.57; N,
12.72; S, 7.28; found: C, 68.40; H, 4.35, N, 12.59; S,
7.48.
22b: Orange crystals (from ethanol), yield 65%
(2.88 g), m.p. 266–268ЊC. IR (tמ/cmמ1) ס 3460, 3360
(NH2), 3055 (CH aromatic), 2983, 2877 (CH3, CH2),
2220 (CN), 1695–1680 (3 CסO), 1641 (CסC). H
NMR d ס 1.33, 1.40 (2t, 6H, 2CH3), 2.25, 2.70 (2m,
1

The Reaction of 2-Amino-3-cyano-4,5,6,7-Tetrahydrobenzo[b]-thiophene with Diethyl Malonate 173
8H, 4CH2), 4.20, 4.25 (2q, 4H, 2CH2), 4.58 (s, 2H,
6.01; N, 8.55; S, 7.64; found: C, 74.61; H, 5.54, N,
8.70; S, 7.69.
NH2), 7.30–7.38 (m, 5H, C6H5), C26H25N3O5S (491.53):
Calcd: C, 63.56; H, 5.08; N, 8.55; S, 6.67; found: C,
63.28; H, 5.39, N, 8.69; S, 6.49.
3-Cyano-2-aminoccarbonyl(ethyl ␣-bromoacet-
at-␣-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene 13
To a hot solution of 3 (2.92 g, 0.01 mol) in acetic acid
(40 mL), bromine (0.5 mL, 0.01 mol) in acetic acid
(10 mL) was added dropwise with continues stirring.
The reaction mixture was left at room temperature
for 3 hours and then poured into ice/water. The solid
product formed was collected by filtration.
13: Pale yellow crystals (from acetic acid), yield
60% (2.23 g), m.p. 180–184ЊC. IR (tמ/cmמ1) ס 3420–
3380 (NH), 2979, 2883 (CH3, CH2), 2220 (CN), 1696,
1680 (2 CסO), 1645 (CסC). 1H NMR d ס 1.33 (t, 3H,
CH3), 2.27, 2.74 (2m, 8H, 4CH2), 4.22 (q, 2H, CH2),
9.21 (s, 1H, NH). C14H15N2O3SBr (371.45): Calcd: C,
45.27; H, 4.07; N, 7.54; S, 8.63; Br, 21.54; found: C,
47.33; H, 4.89, N, 15.29; S, 9.41.
4,7-Diamino-3-ethoxycarbonyl-2-oxo-4,5,6,7-
tetrahydrobenzo-[b]thieno[5,4:4,5]-
pyrimidino[3,2:1,2]pyridine 12, 7-Amino-5-
cyano-3-ethoxycarbonyl-2-oxo-4-phenyl-4,5,6,7-
tetrahydrobenzo-[b]thieno[5,4:4,5]-
pyrimidino[3,2:1,2]pyridine 23a, 7-Amino-3,5-
diethoxycarbonyl-2-oxo-4-phenyl-4,5,6,7-tetra-
hydrobenzo[b]thieno[5,4:4,5]-pyrimidino
[3,2:1,2]pyridine 23b
General Procedure. A suspension of either 11a
(3.58 g, 0.01 mol), 22a (4.44 g, 0.01 mol) or 22b (4.91
g, 0.01 mol) in sodium ethoxide (prepared by dis-
solving sodium metal [0.46 g, 0.02 mol] in absolute
ethanol [50 mL]) was heated in a boiling water bath
for 6 hours. The solid product formed, in each case
upon pouring the mixture into ice/water containing
hydrochloric acid (to pH 6) was collected by
filtration.
4-Amino-3-cyano-3-ethoxycarbonyl-2-oxo-4,5,
6,7-tetrahydrobenzo[b]thieno[2,3-b]pyridine 15
To a hot solution of 13 (3.71 g, 0.01 mol) in ethanol
(60 mL), potassium cyanide (0.76 g, 0.01 mol) solu-
tion (in 10 mL water) was added dropwise with stir-
ring. The reaction mixture was left at room tem-
perature for 3 hours and then poured into ice/water
containing hydrochloric acid (to pH 6), and the
formed solid product was collected by filtration.
15: Yellow crystals (from acetic acid), yield 70%
(2.20 g), m.p. 160–163ЊC IR (tמ/cmמ1) ס 3480–3351
(NH2), 2974, 2881 (CH3, CH2), 2225 (CN), 1715, 1682
12: Pale yellow crystals (from 1,4-dioxane), yield
56% (2.0 g), m.p. 220–223ЊC. IR (tמ/cmמ1) ס 3475–
3346 (2 NH2), 3038 (CH pyridine), 2988, 2895 (CH3,
1
CH2), 1693, 1684 (2 CסO), 1633 (CסC). H NMR d
ס 1.35 (t, 3H, CH3), 2.28, 2.71 (2m, 8H, 4CH2), 4.24
(q, 2H, CH2), 4.99, 5.41 (2s, 4H, 2NH2), 7.09 (s, 1H,
pyridine H-5). 13C NMR d ס 26.3 (ester CH3), 29.3,
30.7 (cyclohexene C-1, C-4), 22.7, 25.4 (cyclohexene
C-2, C-3), 55.2 (ester CH2), 125.2, 131.5, 132.8, 133.1,
133.6, 136.2, 138.9, 140.5, 143.2, 143.7 (thiophene-
C, pyrimidine-C, pyridine-C), 179.6, 180.4 (2 CסO).
C17H18N3O3S (358.39): Calcd: C, 56.97; H, 5.06; N,
15.63; S, 8.94; found: C, 57.33; H, 4.89, N, 15.29; S,
9.41.
1
(2 CסO), 1635 (CסC). H NMR d ס 1.32 (t, 3H,
CH3), 2.25, 2.69 (2m, 8H, 4CH2), 4.23 (q, 2H, CH2),
5.44 (s, 2H, NH2), C15H15N3O3S (317.35): Calcd: C,
56.77; H, 4.76; N, 13.24; S, 10.10; found: C, 56.38; H,
4.66, N, 14.21; S, 10.09.
23a: Yellow crystals (from DMF), yield 60% (2.66
g), m.p. 186–189ЊC. IR (tמ/cmמ1) ס 3444, 3360
(NH2), 3055 (CH aromatic), 2983, 2879 (CH3, CH2),
2-Amino-(2-amino-5-ethoxycarbonylthiazole-
4-yl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]
thiophene 16
1
2222 (CN), 1690, 1685 (2 CסO), 1640 (CסC). H
NMR d ס 1.34 (t, 3H, CH3), 2.25, 2.73 (2m, 8H,
4CH2), 4.23 (q, 2H, CH2), 4.60 (s, 2H, NH2), 7.31–7.40
(m, 5H, C6H5), C24H20N4O3S (444.64): Calcd: C, 64.86;
H, 4.53; N, 12.60; S, 7.21; found: C, 64.69; H, 4.67,
N, 12.77; S, 7.13.
23b: Pale yellow crystals (from DMF), yield 65%
(2.88 g), m.p. 135ЊC. IR (tמ/cmמ1) ס 3469, 3354
(NH2), 3050 (CH aromatic), 2989, 2865 (CH3, CH2),
1700–1680 (3 CסO), 1648 (CסC). 1H NMR d ס 1.36,
1.42 (2t, 6H, 2CH3), 2.22, 2.74 (2m, 8H, 4CH2), 4.23,
4.27 (2q, 4H, 2CH2), 4.66 (s, 2H, NH2), 7.32–7.42 (m,
5H, C6H5), C26H25N3O5S (491.53): Calcd: C, 74.43; H,
A solution of 13 (3.71 g, 0.01 mol) in absolute ethanol
(60 mL) was treated with thiourea (0.76 g, 0.01 mol).
The reaction mixture was heated under reflux for 3
hours and then poured into ice/water. The solid
product, so formed, was collected by filtration.
16: Orange crystals (from acetic acid), yield 81%
(3.33 g), m.p. 120–122ЊC. IR (tמ/cmמ1) ס 3475–3321
(2 NH2), 2994, 2871 (CH3, CH2), 2222 (CN), 1695
(CסO), 1660 (CN) 1645 (CסC). 1H NMR d ס 1.35 (t,
3H, CH3), 2.27, 2.71 (2m, 8H, 4CH2), 4.25 (q, 2H,
CH2), 4.89 (s, 2H, NH2), 8.99 (s, 1H, NH)

174 Mohareb, El-Omran, and Ho
C15H16N4O2S2 (348.34): Calcd: C, 51.73; H, 4.60; N,
16.12; S, 18.39; found: C, 51.66; H, 4.62, N, 16.28; S,
18.44.
20: White crystals (from acetic acid), yield 56%
(2.5 g), m.p. 222–224ЊC. IR (tמ/cmמ1) ס 3585–3325
(OH), 1660 (CסN) 1638 (CסC). H NMR d ס 1.35
1
(t, 3H, CH3), 2.24, 2.72 (2m, 8H, 4CH2), 4.26 (q, 2H,
CH2), 6.77 (s, 1H, CHסC), 10.31 (s, 1H, OH).
C16H16N2O3S2 (348.42): Calcd: C, 55.15; H, 4.63; N,
8.07; S, 18.41; found: C, 55.29; H, 5.01, N, 7.88; S,
18.33.
2-Amino-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]
thieno[5,4:2,3]-pyridino[6,5:4,5]thiazole 18
A solution of 16 (4.12 g, 0.01 mol) in ethanol (50 mL)
containing sodium hydroxide (0.5 g) was heated un-
der reflux for 5 hours and then poured into ice/water
containing hydrochloric acid (to pH 6). The formed
solid product was collected by filtration.
2-Aminocarbonyl(5-acetyl-4-hydroxy-2-phenyl-
aminothiophene-3-yl)-3-cyano-4,5,6,7-tetra-
hydrobenzo[b]thiophene 26, 2-Aminocarbonyl-
ethyl acetato-␣-ylidieno-␣-(3,4-diphenyl-
thiazol-2-ylidieno)-3-cyano-4,5,6,7-tetra-
hydrobenzo[b]thiophene 28a, and 2-Amino-
carbonylethyl acetato-␣-ylidieno-␣-(4-hydroxy-3-
phenylthiazol-2-ylidieno)-3-cyano-4,5,6,7-tetra-
hydrobenzo[b]thiophene 28b
18: Orange crystals (from DMF), yield 60% (1.67
g), m.p. 230–234ЊC. IR (tמ/cmמ1) ס 3555–3331 (OH,
1
NH2), 1666 (CסN) 1638 (CסC). H NMR d ס 2.27,
2.71 (2m, 8H, 4CH2), 5.49 (s, 2H, NH2), 10.31 (s, 1H,
OH). 13C NMR d ס 26.9 (ester CH3), 29.2, 30.9 (cy-
clohexene C-1, C-4), 24.2, 24.5 (cyclohexene C-2, C-
3), 52.9 (ester CH2), 119.2 (CN), 124.5, 130.7, 131.9,
134.9, 140.2, 142.8 (thiophene-C, pyridine-C), 179.8,
180.7 (2 CסO). C12H11N3OS2 (277.36): Calcd: C,
51.96; H, 3.99; N, 15.15; S, 23.12; found: C, 51.87; H,
4.04, N, 14.87; S, 23.09.
General Procedure. To a solution of 3 (2.77 g,
0.01 mol) in dimethylformamide (30 mL) containing
solid potassium hydroxide (0.4 g, 0.01 mol), phenyl
isothiocyanate (1.30 g, 0.01 mol) was added. The re-
action mixture was stirred at room temperature
overnight. Either chloroacetone (0.93 g, 0.01 mol),
phenacylbromide (2.0 g, 0.01 mol), or ethyl bromo-
acetate (1.06 g, 0.01 mol) was added, and the reac-
tion mixture, in each case, was stirred at room tem-
perature overnight. The solid product formed upon
pouring the mixture into ice/water containing hy-
drochloric acid (to pH 6) was collected by filtration.
26: Yellow crystals (from ethanol), yield 66%
(2.87 g), m.p. 140ЊC. IR (tמ/cmמ1) ס 3590–3320 (OH,
2 NH), 3050 (CH aromatic), 2223 (CN), 1695, 1683
2-Ethoxycarbonylacetamido-N-yl-3-(4-hydroxy-
thiazol-2-y)-4,5,6,7-tetrahydrobenzo[b]thio-
phene 19
To a solution of 3 (2.92 g, 0.01 mol) in acetic acid (60
mL), thioglycolic acid (1.20 g, 0.01 mol) was added.
The reaction mixture was heated under reflux for 3
hours and then evaporated in vacuum. The remain-
ing semisolid product was tritutrated with ethanol.
The formed solid product was collected by filtration.
19: Pale yellow crystals (from acetic acid), yield
73% (2.67 g), m.p. 168–70ЊC. IR (tמ/cmמ1) ס 3580–
3355 (OH, NH), 1685, 1680 (2 CסO), 1660 (CסN)
1
(2 CסO), 1660 (CסN) 1638 (CסC). H NMR d ס
2.20 (s, 3H, CH3), 2.23, 2.73 (2m, 8H, 4CH2), 7.29–
7.34 (m, 5H, C6H5), 8.45, 8.59 (2s, 2H, 2NH), 10.07
(s, 1H, OH). 13C NMR d ס 29.2, 31.0 (cyclohexene C-
1, C-4), 24.3, 24.8 (cyclohexene C-2, C-3), 120.1 (CN),
122.0, 122.9, 124.4, 130.8, 131.6, 132.7, 134.9, 136.7,
136.9, 140.0 (two thiophene-C, benzene-C), 178.9,
and 180.4 (CסO). C22H19N3O3S2 (437.52): Calcd: C,
60.39; H, 4.37; N, 9.60; S, 14.66; found: C, 60.44; H,
4.01, N, 9.79; S, 14.39.
1
1644 (CסC). H NMR d ס 1.38 (t, 3H, CH3), 2.26,
2.73 (2m, 8H, 4CH2), 4.24 (q, 2H, CH2), 4.56 (s, 2H,
CH2), 8.88 (s, 1H, NH), 10.01 (s, 1H, OH)
C16H18N2O4S2 (366.43): Calcd: C, 52.44; H, 4.95; N,
7.64; S, 17.50; found: C, 52.77; H, 5.04, N, 7.67; S,
17.32.
28a: Yellow crystals (from ethanol), yield 77%
(4.06 g), m.p. 150ЊC. IR (tמ/cmמ1) ס 3445–3368
(NH), 3055 (CH aromatic), 2220 (CN), 1695, 1683 (2
3-Hydroxy-4-ethoxycarbonylcarboylidieno-
4,5,6,7-tetrahydrobenzo[b]thieno[5,4:4,5]
pyrimidino[6,1:2,3]thiazole 20
1
CסO), 1660 (CסN) 1638 (CסC). H NMR d ס 1.33
A solution of 19 (3.66 g, 0.01 mol) in dimethylform-
amide (30 mL) containing a catalytic amount of tri-
ethylamine (0.5 mL) was heated under reflux for 6
hours and then evaporated in a vacuum. The re-
maining product was triturated with diethyl ether,
and the formed solid product was collected by
filtration.
(t, 3H, CH3), 2.22, 2.70 (2m, 8H, 4CH2), 4.23 (q, 2H,
CH2), 7.31–7.39 (m, 10H, 2 C6H5), 8.48 (s, H, NH),
C29H25N3O3S2 (527.64): Calcd: C, 66.01; H, 4.77; N,
7.96; S, 12.15; found: C, 66.34; H, 4.61, N, 7.77; S,
11.89.
28b: Yellow crystals (from ethanol), yield 59%
(2.75 g), m.p. 177–180ЊC. IR (tמ/cmמ1) ס 3545–3350

The Reaction of 2-Amino-3-cyano-4,5,6,7-Tetrahydrobenzo[b]-thiophene with Diethyl Malonate 175
Jobb, P.; Bai, T. PCT Int Appl WO 1998, 51, 681; Chem
Abstr 1999, 130, 24963v.
[5] Magni, A.; Signorelli, G.; Bocchiola, G. Arzeneim-
Forsch J Drug Res 1994, 44, 1420.
[6] Imming, P. Arch Pharm 1995, 328.
[7] Nanteuil, G. D.; Herve, Y.; Duhault, J.; Espinal, J.;
Boulanger, M.; Ravel, D. Arzeneim-Forsch J Drug Res
1995, 45, 1175.
[8] Albuquerque, J. F. C.; Albuquerque, A.; Azevedo, C.
C.; Thomasson, F.; Galdino, L. S.; Chante-Grel, J.; Ca-
tanho, M. T. J.; Pitta, R.; Luu-Due, C.; Pharmazie
1995, 50, 387.
[9] El-Feky, S. A.; Abdel-Samii, Z. K.; Pharmazie 1995,
50, 341.
[10] Mohareb, R. M.; Sherif, S. M.; Sami, A. M.; Phospho-
rus Sulfer Silicon 1995, 101, 57.
(OH, NH), 3050 (CH aromatic), 2220 (CN), 1690,
1681 (2 CסO), 1665 (CסN) 1640 (CסC). 1H NMR d
ס 1.36 (t, 3H, CH3), 2.25, 2.73 (2m, 8H, 4CH2), 4.27
(q, 2H, CH2), 7.28–7.36 (m, 5H, C6H5), 8.71 (s, H,
NH), 10.27 (s, 1H, OH). C23H21N3O4S2 (467.54):
Calcd: C, 59.08; H, 4.53; N, 8.99; S, 13.72; found: C,
58.84; H, 4.68, N, 9.29; S, 13.86.
REFERENCES
[1] Mohareb, R. M.; Manhi, F. M. Heteroat Chem 2000,
11, 403.
[2] Zohdi, H. F.; Wardakhan, W. W.; Doss, S. H.;
Mohareb, R. M. J Chem Research (S) 1996, 440; (M)
1996, 2526.
[3] Sherif, S. M.; Wardakhan, W. W.; Mohareb, R. M. J
Chem Research (S) 1996, 356; (M) 1996, 1970.
[4] Bakonyi, M.; Csatari, M. N.; Molnar, L.; Makovi, Z.;
[11] Mohareb, R. M.; Wardakhan, W. W.; El-Ablack, F. Z.
J Chem Research (S) 1994, 126; (M) 1994, 747.
[12] El-Kousy, S. M.; Mohareb, R. M.; Sherif, S. M. J
Chem Research (S) 1993, 312; (M) 1993, 1981.
[13] Mohareb, R. M. Gazzetta Chem Ital 1992, 122, 147.